Increased O-Linked N-Acetylglucosamine Modification of NF-IeB and Augmented Cytokine Production in the Placentas from Hyperglycemic Rats
Increased O-Linked N-Acetylglucosamine Modification of NF-IeB and Augmented Cytokine Production in the Placentas from Hyperglycemic Rats
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DOI：
10.1007/s10753-017-0620-7
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发表时间：
2017-10-01
期刊：
影响因子：
5.1
通讯作者：
Giachini, Fernanda R.
中科院分区：
文献类型：
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作者：
Dela Justina, Vanessa;Goncalves, Jessica S.;Giachini, Fernanda R.
由核因子-kappa B激活引起的炎症可能是经典(典型)途径引起的，伴随着I-kappa B抑制剂的断开和随后的核转位，或者，通过调节蛋白或核因子-kappa B亚单位的翻译后修饰(非典型途径)。我们推测，高血糖导致胎盘组织中核因子-kappa B与O-连接N-乙酰氨基葡萄糖(O-GlcNAc)的糖基化增加，导致促炎症细胞因子的产生增加，最终导致胎盘功能障碍和胎儿生长受限。给雌性Wistar大鼠一次性注射链脲佐菌素(40 mg/kg)或赋形剂，分别造成高血糖和正常血糖。3天后交配，确认妊娠。于妊娠第21天采集胎盘组织。胎盘组织中p65亚单位的表达差异无统计学意义。然而，高血糖组p65亚基的核转位增加，显示出更大的核因子-kappaB的激活。高血糖大鼠胎盘组织中I-kappa B表达减少，磷酸化I-kappa B-Ser32表达增加，经典的核因子-kappaB活性增强。免疫沉淀实验表明，在高血糖大鼠胎盘中发现O-GlcNAc修饰蛋白的增强修饰，p65亚基是O-GlcNAc的关键靶点。高血糖大鼠胎盘组织中肿瘤坏死因子-α和白介素6的表达增加。此外，在高血糖条件下，胎盘重量增加，而胎儿体重减少。TNF-α、IL-6与胎盘重量呈正相关，与胎盘重量、胎盘效率呈负相关。因此，在高血糖条件下，胎盘中O-GlcNAc对核因子-kappaB活性的调节作用被证实，从而导致炎性细胞因子加重引起的胎儿和胎盘功能障碍。
Inflammation as a result of NF-kappa B activation may result from the classical (canonical) pathway, with disconnection of the I kappa B inhibitor and subsequent nuclear translocation or, alternatively, by post-translational modifications of modulatory proteins or NF-kappa B subunits (non-canonical pathway). We hypothesized that hyperglycemia-induced increased glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) of NF-kappa B in placental tissue leads to augmented production of pro-inflammatory cytokines, culminating in placental dysfunction and fetal restriction growth. Single injections of streptozotocin (40 mg/kg) or vehicle were used to induce hyperglycemia or normoglycemia, respectively, in female Wistar rats. After 3 days, rats were mated and pregnancy confirmed. Placental tissue was collected at 21 days of pregnancy. Placental expression of p65 subunit was similar between groups. However, nuclear translocation of p65 subunit, showing greater activation of NF-kappa B, was increased in the hyperglycemic group. Reduced expression of I kappa B and increased expression of phosphorylated I kappa B-Ser32 were observed in the placenta from hyperglycemic rats, demonstrating increased classical NF-kappa B activation. Augmented modification of O-GlcNAc-modified proteins was found in the placenta from hyperglycemic rats and p65 subunit was a key O-GlcNAc target, as demonstrated by immunoprecipitation. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) expressions were increased in the placenta from hyperglycemic rats. Furthermore, placental weight was increased, whereas fetal weight was decreased under hyperglycemic conditions. TNF-alpha and IL-6 demonstrated positive correlations with placental weight and negative correlations with fetal weight and placental efficiency. Therefore, under hyperglycemic conditions, a modulatory role of O-GlcNAc in NF-kappa B activity was demonstrated in the placenta, contributing to fetal and placental dysfunction due to inflammatory cytokine exacerbation.